Consumer medicine information

Zelboraf

Vemurafenib

BRAND INFORMATION

Brand name

Zelboraf

Active ingredient

Vemurafenib

Schedule

What is in this leaflet

This leaflet answers some common questions about Zelboraf tablets.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Zelboraf against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Zelboraf is used for

Zelboraf contains the active ingredient vemurafenib.

Zelboraf belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents.

Zelboraf is used to treat metastatic melanoma (a type of skin cancer that has spread to other parts of the body). It can only be used if your melanoma has a change (mutation) in the BRAF gene. Your doctor will have tested you for this gene. This change has been shown to be involved in the development of melanoma.

Zelboraf works by targeting proteins made from the BRAF gene to slow down the development of your cancer.

Ask your doctor if you have any questions about why Zelboraf has been prescribed for you.

Zelboraf is not addictive.

This medicine is available only with a doctor's prescription.

Before you take Zelboraf

When you must not take it

Do not take Zelboraf if:

you are allergic (hypersensitive) to vemurafenib or any ingredients listed at the end of this leaflet
Some of the symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

the package is torn or shows signs of tampering

If the package is damaged, return it to your pharmacist for disposal.

the expiry date (EXP) printed on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should start taking Zelboraf, talk to your doctor.

Before you start to take it

Tell your doctor if:

you have a heart disorder,

such as abnormal electrical signal called "prolongation of the QT interval". Your doctor will test to check that your heart is working properly before and during your treatment with Zelboraf. If necessary, your doctor may decide to interrupt your treatment temporarily or stop it altogether.

you have liver problems

Before and regularly during your treatment, your doctor will do some blood tests to monitor your liver function. If necessary, your doctor may decide to reduce your dose, interrupt your treatment temporarily or stop it altogether.

you have kidney problems

Kidney problems may affect the activity of Zelboraf. Your doctor will do some blood tests to monitor your kidney function.

you are pregnant or plan to become pregnant

Tell your doctor if you are pregnant or plan to become pregnant.
Zelboraf is not recommended for use during pregnancy. There is no information about the safety of Zelboraf in pregnant women. However if there is a need to take Zelboraf when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.
Women of childbearing potential and men should use adequate contraception during treatment and for 6 months after the end of treatment with Zelboraf.

you have been told that you have low blood levels of potassium, calcium, or magnesium in your blood

These levels may need to be corrected before treatment with Zelboraf begins.

you have been previously diagnosed with other types of cancer
you are breast-feeding or plan to breast-feed

It is not known whether Zelboraf passes into breast milk. Breast-feeding is not recommended during treatment with Zelboraf.

you have previously received radiation treatment
you are allergic to any other medicines, foods, dyes or preservatives

If you have not told your doctor about any of the above, tell him or her before you start taking Zelboraf.

Use in Children

Zelboraf is not recommended for use in children and adolescents. The safety and effectiveness in people younger than 18 years old have not been established.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought from a pharmacy, supermarket or health food shop. Tell your doctor if you are receiving treatment for any other medical conditions.

Zelboraf may interfere with some medicines. These include:

ipilimumab, a medicine used to treat metastatic melanoma
warfarin, a medicine used to prevent blood clots
medicines that are mainly eliminated by or affect a metabolising protein called CYP3A4 such as;
- ketoconazole, itraconazole or voriconazole, medicines used to treat fungal infections
- atazanavir, saquinavir, ritonavir, nelfinavir or indinavir, medicines used to treat HIV infection
- phenytoin, carbamazepine or phenobarbital, medicines used to treat convulsions
- rifampicin, rifabutin, rifapentine, clarithromycin or telithromycin, medicines used to treat bacterial infections
- nefazodone or herbal medicines derived from St. John's Wort, used to treat depression
- some oral, injectable, or implantable contraceptives, for example "the Pill", used for birth control
medicines that are mainly eliminated by a metabolizing protein called CYP1A2 such as;
- caffeine, a stimulant
- olanzapine, clozapine, medicines used in treat schizophrenia and depression
- theophylline, a medicine used to treat asthma
- tizanidine, a medicine used as a muscle relaxant
medicines that influence, or are affected by, a protein called P-glycoprotein such as;
- verapamil, a medicine used to treat high blood pressure and angina (chest pain)
- cyclosporin, a medicine used to suppress the immune system
- dronedarone or digoxin, medicines used treat heart problems
medicines that may affect your heartbeat such as:
- those used to treat heart rhythm problems, such as amiodarone
- those used to treat depression, such as amitriptyline or imipramine
- those used to treat bacterial infections, such as azithromycin and clarithromycin
- ondansetron or domperidone, medicines used to treat nausea and vomiting.
medicines that influence, or are affected by, a protein called BCRP such as;
- methotrexate, medicine used to treat arthritis and some types of cancer
- mitoxantrone, a medicine used to treat some types of cancer
- rosuvastatin, a medicine used to lower high cholesterol

These medicines may be affected by Zelboraf, or may affect how well Zelboraf works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

This is not a complete list. Zelboraf may interfere with other medicines. Please tell your doctor or pharmacist if you are taking other medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Zelboraf.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to take Zelboraf

Always take Zelboraf exactly as your doctor has told you. You should check with your doctor if you are not sure.

How much to take

The normal dose of Zelboraf is 4 tablets twice a day. Take 4 tablets in the morning, then 4 tablets in the evening, about 12 hours later.

If you experience side effects, your doctor may need to lower the dose to carry on your treatment.

Always take Zelboraf exactly as your doctor has told you. Your doctor's directions may differ from the information in this leaflet.

How to take it

Swallow the tablets whole with a glass of water.

Take Zelboraf on an empty stomach either at least 1 hour before or at least 2 hours after a meal in the morning and evening. Food may interfere with the absorption of Zelboraf.

Do not chew or crush the tablets.

How long to take it

How long you will be treated with Zelboraf depends on how you are responding to treatment. Your doctor will discuss this with you.

Continue taking Zelboraf until your doctor tells you to stop.

If you forget to take it

If you forget a dose take your dose as soon as you remember it.

If it is less than 4 hours before your next dose, skip the missed dose. Then take the next dose at the usual time.

Do not take a double dose to make up for a forgotten dose. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor, nurse or pharmacist.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you vomit after taking it

If you vomit after taking Zelboraf, do not take the same dose again. Then take the next dose at the usual time.

If you use too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (Australia - telephone 13 11 26; New Zealand - telephone 0800 764 766) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have used too much Zelboraf, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Taking too much Zelboraf may make some side effects more likely or more severe.

Keep telephone numbers for these places handy.

While you are taking Zelboraf

Things you must do

Use Zelboraf exactly as your doctor has prescribed.

If you are about to be started on any new medicine or start radiation treatment, remind your doctor and pharmacist that you are taking Zelboraf.

Tell all doctors, dentists and pharmacists who are treating you that you are receiving Zelboraf.

Tell your doctor if you notice changes in your skin such as;

a new wart
a skin sore or reddish bump
a sore that bleeds or does not heal.

Regularly during treatment and for up to 6 months after your treatment, your doctor needs to check your skin for a type of cancer called cutaneous squamous cell carcinoma. There is a high risk of developing these skin cancers while taking Zelboraf.

In clinical trials, one in four patients developed these skin cancers. These skin cancers may develop as early as the first month of Zelboraf treatment. Factors that increase your risk of developing these cancers are being 65 years old or older, prior skin cancer and long-term sun exposure.

Usually, this change appears on sun damaged skin, remains local and can be cured by surgical removal. If your doctor finds this type of skin cancer, they may treat it or may send you to another doctor for treatment.

In addition, check your skin and tell your doctor right away about any changes. You may develop new melanomas while taking Zelboraf. These lesions are usually removed by surgery and you can continue your treatment.

Avoid going out in the sun. If you are taking Zelboraf you may become more sensitive to sunlight and get symptoms of sunburn (such as redness, itching, swelling and blistering) more easily or get sunburns that can be severe.

To help protect against sunburn, if you do plan to go into the sun:

wear clothing which protects your skin, including head, face, arms and legs
use a broad spectrum (UVA/UVB) sunscreen and lip balm (minimum of SPF 30+, re-applied every 2 - 3 hours)

Tell your doctor if you become pregnant while using Zelboraf.

Women of childbearing potential and men should use adequate contraception during treatment and for 6 months after the end of treatment with Zelboraf.

Tell your doctor if you are breast-feeding while being treated with Zelboraf.

Tell your doctor if, for any reason, you have not used Zelboraf exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel Zelboraf is not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may perform tests to help guide your treatment.

Things you must not do

Do not stop taking Zelboraf or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Do not give Zelboraf to anyone else even if they have the same condition as you.

You should not breast-feed your infant during treatment with Zelboraf. It is not known whether Zelboraf crosses into human breast milk.

Things to be careful of

Be careful driving or operating machinery until you know how Zelboraf affects you.

Zelboraf may affect the ability to drive or operate machinery due to side effects, which may be experienced while taking Zelboraf, as such

feeling tired (fatigue)
dizziness
eye problems.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving Zelboraf.

Zelboraf helps many people with metastatic melanoma but it may have unwanted side effects.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

red skin rashes, itching, dry or scaly skin, and hardened or thickened areas of the skin
painful red lumps or patches of skin that may appear darker or harder than usual
skin problems including warts
sunburn
increased sensitivity to light
loss of appetite and weight loss
headache
changes in the way things taste
drooping eyelid and sagging muscles on one side of the face caused by a paralysed nerve in the face (often reversible)
tingling, burning feelings, or pain in your hands or feet
diarrhoea
constipation
hair loss
joint, muscle, or back pain
unusual weakness or lack of energy
feeling sick (nausea), vomiting
feeling tired (fatigue)
fever
excess fluid (swelling), usually in the legs
cough
frequent infections such as fever, severe chills, sore throat or mouth ulcers
thickening or appearance of visible cords, bands or lumps in the palm of one or both hands or feet

These are the more common side effects of Zelboraf.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

difficulty breathing, chest tightness or wheezing
swelling of the face, lips or mouth
severe skin rash, itching, hives
severe blisters or bleeding of your lips, mouth, nose, or eyes
a severe skin reaction starting with painful red areas, then large blisters and ends with peeling of layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell.
fever associated with a mild to severe skin rash
severe light-headedness or dizziness or feel your heart is beating irregularly or fast
problems with your eyes or eyesight such as blurred or altered vision, irritated eyes, eye pain or redness
yellowing of the skin and eyes
light coloured bowel motions
dark coloured urine
severe upper stomach pain, often with nausea and vomiting (signs of inflammation of the pancreas)

These are serious side effects. You may need urgent medical attention.

Tell your doctor as soon as possible if you notice any changes in your skin.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Ask your doctor or pharmacist if you don't understand anything in this list.

After using Zelboraf

Storage

Keep Zelboraf in a cool dry place where the temperature stays below 30 °C.

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Do not store Zelboraf, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Zelboraf where young children cannot reach it. A locked cupboard at least 1.5 metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Zelboraf, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product Description

Availability

Zelboraf 240 mg film-coated tablets are available in packs of 56 tablets (7 blisters of 8 tablets).

What it looks like

Zelboraf tablets are oval, biconvex, pinkish white to orange white tablets with "VEM" engraved on one side.

Ingredients

Active ingredient -

vemurafenib

Inactive ingredients

croscarmellose sodium
colloidal anhydrous silica
magnesium stearate
hydroxypropylcellulose
hypromellose acetate succinate

The film-coating contains:

polyvinyl alcohol
titanium dioxide CI77891
macrogol 3350
talc, purified
iron oxide red CI77491

Distributor

Zelboraf is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

Zelboraf is distributed in New Zealand by:

Roche Products (New Zealand) Limited
PO Box 109113 Newmarket
Auckland 1149
NEW ZEALAND
Medical enquiries: 0800 276 243

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Number
AUST R 183674

This leaflet was prepared on 25 March 2020

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Zelboraf

Active ingredient

Vemurafenib

Schedule

1 Name of Medicine

Vemurafenib.

6.7 Physicochemical Properties

Chemical structure.

Vemurafenib is designated chemically as N-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b] pyridin-3-carbonyl]-2,4-difluorophenyl} propane-1-sulfonamide.
The empirical formula of vemurafenib is C₂₃H₁₈ClF₂N₃O₃S and its molecular weight is 489.9.
Vemurafenib is a white to off-white crystalline solid. It is practically insoluble in aqueous media. The pKa (acidic) is 7.9 and 11.1 and the log P (water) is 3.0.

CAS number.

918504-65-1.

2 Qualitative and Quantitative Composition

Each tablet contains 240 mg vemurafenib (as a coprecipitate of vemurafenib and hypromellose acetate succinate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablets.
Oval, biconvex, pinkish white to orange white tablets with "VEM" engraved on one side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15.

Mechanism of action.

Zelboraf is a protein kinase inhibitor, selective for the activating mutation of the oncogenic BRAF serine-threonine kinase enzyme.
Vemurafenib is an inhibitor of BRAF serine-threonine kinase, and other kinases, such as CRAF, ARAF, SRMS, ACK1, MAP4K5 and FGR. Mutations in the BRAF gene result in constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth factors.
Preclinical data generated in biochemical assays demonstrated that vemurafenib can inhibit BRAF kinases with activating codon 600 mutations (see Table 7).

This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays the inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and V600K mutated cell lines) ranged from approximately 0.015 to 1 microM whereas the IC50 against BRAF wild type cell lines were > 10 microM.

Clinical trials.

The efficacy of Zelboraf has been evaluated in 337 patients from a phase III randomised, active controlled clinical trial and 132 patients from a phase II single arm clinical trial. Prior to study enrolment, tumour specimens from all patients were tested for the presence of a BRAF V600 mutation using a real time polymerase chain reaction assay. During clinical trials the cobas 4800 BRAF V600 Mutation Test was used to assess the BRAF mutation status of DNA isolated from formalin fixed, paraffin embedded tumour tissue. Please refer to the package insert of the cobas 4800 BRAF V600 mutation test, or other approved test kits for detailed information.
Among the tumour specimens sequenced retrospectively from enrolled patients, the majority (92%) were BRAF V600E mutation-positive and 8% carried non-E mutations (primarily V600K). The efficacy and safety of Zelboraf in patients with tumours expressing BRAF V600 non-E mutations have not been convincingly established.

Treatment naïve patients (study NO25026, BRIM3).

An open label, multicenter, multinational, randomised phase III study supports the use of Zelboraf in previously untreated patients with BRAF V600 mutation positive unresectable stage IIIC or stage IV melanoma. In this study, patients were randomised to treatment with Zelboraf (960 mg, orally, twice daily) or dacarbazine (1000 mg/m² every 3 weeks, intravenously).
A total of 675 patients were randomised to Zelboraf (n = 337) or dacarbazine (n = 338). Randomisation was stratified according to disease stage, lactate dehydrogenase (LDH), ECOG performance status and geographic region. Baseline characteristics were well balanced between treatment groups. For patients randomised to Zelboraf, most patients were male (59%) and Caucasian (99%), the median age was 56 years (28% were ≥ 65 years old), all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1c disease (66%). The coprimary efficacy endpoints of the study were overall survival (OS) and progression free survival (PFS). Key secondary endpoints included confirmed best overall response rate (BORR) and response duration.
Statistically significant and clinically meaningful improvements were observed in the coprimary endpoints of OS (p < 0.0001) and PFS (p < 0.0001) (unstratified log-rank test) based on the prespecified interim analysis at the data cut off of 30 December 2010. The median follow-up time for OS in the Zelboraf group at the 30 December 2010 data cut off was 3.75 months (range 0.3 - 10.8 months) and in the dacarbazine group was 2.33 months (range < 0.1 - 10.3 months). At the time of analysis, Kaplan-Meier estimates of median OS for both treatment arms were considered unreliable due to the small number of patients in follow-up (< 10%) beyond month 7. The secondary endpoint of confirmed BORR [complete response (CR) + partial response (PR)], as assessed by the investigator, was significantly improved (p < 0.0001) in the Zelboraf arm (48.4%) (95% CI: 41.6%, 55.2%) compared to the dacarbazine arm (5.5%) (95% CI: 2.8%, 9.3%). There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the Zelboraf arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm. Stable disease assessed according to RECIST 1.1 was observed in 37% of Zelboraf treated patients and 24% of dacarbazine treated patients.
Improvement in OS, PFS and confirmed BORR in favour of Zelboraf treatment were generally observed across subgroups (age, sex, baseline LDH, ECOG performance status, metastatic disease stage) and geographic regions.
The proportion of patients with improvement in the physician's assessment of performance status was higher in the Zelboraf group (63.4%) (95% CI: 57%, 69%) than in the dacarbazine group (20.2%) (95% CI: 15%, 26%).
After the prespecified interim analysis with a December 30, 2010 data cut-off the study was modified to permit dacarbazine patients to cross over to receive Zelboraf. Post hoc survival analyses were undertaken thereafter as described in Table 8. At the time of the December 20, 2012 data cut-off analysis the median follow-up time in the Zelboraf arm was 13.4 months (range 0.4 to 33.3 months). The Kaplan-Meier estimate of median OS for Zelboraf was 13.6 months (95% CI: 12.0, 15.3). (See Figure 1.)

Table 9 and Figure 2 show the progression-free survival in treatment-naïve patients with BRAF V600 mutation positive melanoma.

Patients who failed at least one prior systemic therapy (study NP22657, BRIM2).

A phase II single arm, multicenter, multinational study was conducted in 132 metastatic melanoma patients with BRAF V600 mutation positive tumours who had received at least one prior therapy. Patients received 960 mg Zelboraf twice daily. The median age was 52 years old with 19% of patients being older than 65 years old. The majority of patients were male (61%), Caucasian (99%), and had stage M1c disease (61%). Forty-nine percent of patients had failed ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 - 11.3 months).
The primary endpoint of confirmed BORR (CR + PR) as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). The median time to response was 1.4 months, with 75% of responses occurring by 1.6 months of treatment.
Efficacy results are summarised in Table 10.

Patients with brain metastases.

An open-label, single-arm, multicenter, phase II study (n = 146) of Zelboraf was conducted in adult patients with histologically confirmed metastatic melanoma harbouring the BRAF V600 mutation and with brain metastases. Patients could be either symptomatic or asymptomatic for their brain metastases. The study included two simultaneously enrolling cohorts:
Previously untreated patients (cohort 1: n = 90): Patients who had not received previous treatment for brain metastases; prior systemic therapy for metastatic melanoma was allowed.
Previously treated patients (cohort 2: n = 56): Patients who had been previously treated for their brain metastases and had progressed following this treatment. For patients treated with stereotactic radiotherapy (SRT) or surgery, a new RECIST-assessable brain lesion must have developed following this prior therapy.
The median age of the patients was 54 years (range 26 to 83 years), and was similar in the two cohorts. The majority of patients were men (61.6%) and similarly distributed between the two cohorts. A total of 135 patients (92.5%) were reported as white, with the race of 11 patients (7.5%) not reported due to local regulations. The median number of brain target lesions at baseline was 2 (range 1 to 5), in both cohorts.
The primary objective of the study was to evaluate the efficacy of Zelboraf using best overall response rate (BORR) in the brain of metastatic melanoma patients with previously untreated brain metastases, as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
Secondary objectives included an evaluation of the efficacy of Zelboraf using BORR in the brain of previously treated patients, duration of response (DOR), progression-free survival (PFS) and overall survival (OS) in patients with melanoma metastatic to the brain. (See Table 11.)

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) parameters for vemurafenib were determined using non compartmental analysis in a phase I and a phase III study. Mean C_max, C_minand AUC_0-12hr were approximately 62 microgram/mL, 53 microgram/mL and 600 microgram.h/mL, respectively. Population PK analysis using pooled data from 458 patients estimated the median of the steady-state C_max, C_min and AUC to be 62 microgram/mL, 59 microgram/mL and 734 microgram.h/mL, respectively. The median accumulation ratio estimate for a twice daily regimen is 7.36. The PK of vemurafenib is shown to be dose proportional between 240 and 960 mg twice daily dosing, and population PK analysis also confirmed that the PK of vemurafenib is linear.

Absorption.

Vemurafenib is absorbed with a median T_max of approximately 4 hours following a single 960 mg dose (four 240 mg tablets). Vemurafenib exhibits marked accumulation after repeat dosing at 960 mg twice daily with high interpatient variability. In the phase II study mean vemurafenib plasma concentration at 4 hours post dose increased from 3.6 microgram/mL on day 1 to 49.0 microgram/mL on day 15 (range 5.4 - 118 microgram/mL).
The bioavailability of vemurafenib at steady state was 57.8% (geometric mean).
At steady state (reached by day 15 in 80% of patients), the mean vemurafenib exposure in plasma is stable (concentrations before and 2 - 4 hours after the morning dose) as indicated by the mean ratio of 1.13. Similar marked interpatient variability in plasma exposure was observed at steady-state independent of dose reduction.
Following oral dosing, the absorption rate constant for the population of metastatic melanoma patients is estimated to be 0.19 hr^-1 (with 101% inter-patient variability).
Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. The geometric mean ratios between the fed and fasted states for C_max and AUC were 2.5 and 4.6 to 5.1-fold, respectively. The median T_max was increased from 4 to 7.5 hours when a single vemurafenib dose was taken with food. Safety and efficacy data from pivotal studies were collected from patients taking vemurafenib with or without food.
The effect of food on steady-state vemurafenib exposure is currently unknown.

Distribution.

The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 91 L (with 64.8% interpatient variability). It is highly bound to human plasma proteins in vitro (> 99%).

Metabolism.

The relative proportions of vemurafenib and its metabolites were characterised in a human mass balance study with a single dose of ¹⁴C-labeled vemurafenib administered orally at steady state.
On average, 95% of the dose was recovered within 18 days. The majority (94%) in faeces, with < 1% recovered in urine. While CYP3A4 is the primary enzyme responsible for the metabolism of vemurafenib in vitro, conjugation metabolites (glucuronidation and glycosylation) were also identified in humans. However, the parent compound was the predominant component (95%) in plasma. Although metabolism does not appear to result in a relevant amount of metabolites in plasma, the importance of metabolism for excretion cannot be excluded. Coadministration of rifampin, a strong CYP3A4 inducer, significantly decreased the plasma exposure of vemurafenib (AUC) by approximately 40% following a single 960 mg dose of vemurafenib, suggesting CYP3A4 pathway could be important elimination pathway for vemurafenib. Coadministration of itraconazole, a strong CYP3A4 inhibitor, increased steady state vemurafenib AUC by approximately 40%.

Excretion.

The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 29.3 L/day (with 31.9% interpatient variability). The median of the individual elimination half-life estimates for vemurafenib is 56.9 hours (the 5^th and 95^th percentile range).

Pharmacokinetics in special populations.

Paediatrics.

Limited pharmacokinetic data from six adolescent patients aged 15 to 17 with stage IIIC or IV BRAF V600 mutation positive melanoma suggest that vemurafenib pharmacokinetic characteristics in adolescents are generally similar to those in adults. However, no conclusion can be made due to the limited amount of data (see Section 4.2 Dose and Method of Administration for special dosage instructions).

Elderly.

Based on the population pharmacokinetic analysis, age has no statistically significant effect on vemurafenib pharmacokinetics.

Hepatic impairment.

Based on preclinical data and the human mass balance study, vemurafenib is eliminated primarily via the liver. No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, increases in AST, ALT, and total bilirubin up to three times the upper limit of normal did not influence the apparent clearance of vemurafenib. The potential need for dose adjustment in patients with severe hepatic impairment cannot be determined as clinical and pharmacokinetic data are insufficient to determine the effect of metabolic or excretory hepatic impairment on vemurafenib pharmacokinetics. Caution is recommended in these patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, mild and moderate renal impairment did not influence the apparent clearance of vemurafenib (creatinine clearance > 30 mL/min). The potential need for dose adjustment in patients with severe renal impairment (creatinine clearance < 29 mL/min) cannot be determined as clinical and pharmacokinetic data are insufficient (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Gender.

In the population pharmacokinetic analysis, gender was found to be statistically significant in explaining the inter-patient variability, with a 17% greater apparent clearance (CL/F) and a 48% greater apparent volume of distribution (V/F) in males. However, results from the population analysis have shown that the differences in exposure are relatively small (with an estimated median 12-hour steady-state AUC and C_max of 792 microgram.h/mL and 67 microgram/mL in females and 696 microgram.h/mL and 63 microgram/mL in males, respectively), indicating that there is no need to dose adjust based on gender.

5.3 Preclinical Safety Data

Genotoxicity.

Standard genotoxicity studies in in vitro assays (bacterial mutation [Ames assay], human lymphocyte chromosome aberration) and in the in vivo rat bone marrow micronucleus test conducted with vemurafenib were all negative.

Carcinogenicity.

No carcinogenicity studies have been performed to establish the carcinogenic potential of Zelboraf.

4 Clinical Particulars

4.1 Therapeutic Indications

Zelboraf is indicated for the treatment of unresectable stage IIIC or stage IV metastatic melanoma positive for a BRAF V600 mutation.

4.3 Contraindications

Zelboraf is contraindicated in patients with hypersensitivity to vemurafenib or to any of its excipients.

4.4 Special Warnings and Precautions for Use

General.

Before taking Zelboraf, patients must have BRAF V600 mutation positive tumour status confirmed by a TGA approved assay performed by a NATA accredited laboratory.
The efficacy and safety of Zelboraf in patients with tumours expressing BRAF V600 non-E mutations have not been convincingly established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Malignancies.

Cutaneous squamous cell carcinoma (cuSCC).

Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects)). CuSCC usually occurred early in the course of treatment. Potential risk factors associated with cuSCC in Zelboraf clinical trials included age (≥ 65 years old), prior skin cancer, and chronic sun exposure. Cases of cuSCC were typically managed with simple excision, and patients were able to continue treatment without dose adjustment.
It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care. Monitoring should continue for up to 6 months following discontinuation of Zelboraf or until initiation of another antineoplastic therapy.
Patients should be instructed to inform their physicians upon the occurrence of any skin changes, including rash and photosensitivity.

Noncutaneous squamous cell carcinoma (non-cuSCC).

In clinical studies rare cases of squamous cell carcinoma of the head and neck (tongue and tonsils) have been reported. Patients should undergo a head and neck examination, consisting of at least a visual inspection of oral mucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment. Pelvic (for women) and anal examinations are recommended before and at the end of treatment or when considered clinically indicated. As per routine disease management, chest CT scans performed prior to initiation of treatment and every 6 months during treatment should be reviewed for non-cuSCC. Following discontinuation of Zelboraf, monitoring for non-cuSCC should continue for up to 6 months or until initiation of another antineoplastic therapy. Abnormal findings should be evaluated as clinically indicated.

New primary malignant melanoma.

New primary malignant melanomas have been reported in clinical trials. Cases were managed with resection and patients continued on treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above for cutaneous squamous cell carcinoma.

Hypersensitivity reactions.

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with Zelboraf and upon reinitiation of treatment (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). Severe hypersensitivity reactions included generalised rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, Zelboraf treatment should be permanently discontinued.

Dermatologic reactions.

Severe dermatologic reactions have been reported in patients receiving Zelboraf, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). In patients who experience a severe dermatologic reaction, Zelboraf treatment should be permanently discontinued.

Photosensitivity.

Mild to severe photosensitivity was reported in patients who were treated with Zelboraf in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). All patients should be advised to avoid sun exposure while taking Zelboraf. While taking Zelboraf, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sun screen and lip balm (SPF ≥ 30+) when outdoors to help protect against sunburn.
For photosensitivity, grade 2 (intolerable) or greater adverse events, dose modifications are recommended (see Section 4.2 Dose and Method of Administration).

Dupuytren's contracture and plantar fascial fibromatosis.

Dupuytren's contracture and plantar fascial fibromatosis have been reported with Zelboraf. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren's contracture have also been reported (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Events should be managed with dose reduction, treatment interruption, or with treatment discontinuation (see Section 4.2 Dose and Method of Administration, Dose modifications).

Ophthalmologic reactions.

Serious ophthalmologic reactions including uveitis have been reported in patients treated with Zelboraf. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Additionally, blurry vision, iritis, photophobia and retinal vein occlusion have been reported. Patients should be monitored routinely for ophthalmologic reactions, and be advised to urgently seek medical attention in the event of acute onset eye pain and/or change in visual acuity.

QT prolongation.

Exposure dependent QT prolongation was observed in an uncontrolled, open label phase II QT substudy in previously treated patients with metastatic melanoma (see Section 4.8 Adverse Effects (Undesirable Effects)). QT prolongation may lead to an increased risk of ventricular arrhythmias including torsade de pointes. Treatment with Zelboraf is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.
ECG and electrolytes should be monitored before treatment with Zelboraf and after dose modification. Further monitoring should occur monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with Zelboraf is not recommended in patients with QTc > 500 ms. If, during treatment, the QTc exceeds 500 ms (CTCAE ≥ grade 3), Zelboraf treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Reinitiation of treatment should not occur until the QTc decreases below 500 ms and should be reinitiated at a lower dose, as described (see Section 4.2 Dose and Method of Administration, Dose modifications). Permanent discontinuation of Zelboraf treatment is recommended if, after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pretreatment values.

Pancreatitis.

Pancreatitis has been reported in Zelboraf treated subjects, generally occurring within two weeks after initiation of Zelboraf treatment. Unexplained abdominal pain should be promptly investigated, including appropriate diagnostic tests for pancreatitis. Patients should be closely monitored when restarting Zelboraf after an episode of pancreatitis.

Liver injury.

Liver injury, including cases of severe liver injury, has been reported with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Liver laboratory abnormalities may occur with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical trials). Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured before initiation of treatment and monitored monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or with treatment discontinuation (see Section 4.2 Dose and Method of Administration, Dose modifications).

Concurrent administration with ipilimumab.

In a phase I trial, asymptomatic grade 3 increases in transaminases and bilirubin were reported with concurrent administration of ipilimumab (3 mg/kg) and Zelboraf (960 mg twice daily or 720 mg twice daily). Based on these data, the concurrent administration of ipilimumab and Zelboraf is not recommended outside of a clinical trial.

Use in renal impairment.

Limited data are available in patients with renal impairment. A risk for increased exposure in patients with severe renal impairment cannot be excluded (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Other malignancies.

Based on its mechanism of action, Zelboraf may cause progression of cancers associated with RAS mutations (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). Zelboraf should be used with caution in patients with a prior or concurrent cancer associated with RAS mutation.

Use in hepatic impairment.

Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver, patients with severe hepatic impairment may have increased exposure (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Cases of liver injury, including severe liver injury, have been reported with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use, Liver injury for important information on monitoring and management).

Paediatric use.

The safety and efficacy of Zelboraf in paediatric patients below 18 years of age have not been established.

Use in the elderly.

Ninety-four (94) of 336 patients (28%) with unresectable or metastatic melanoma treated with Zelboraf in the phase III study were ≥ 65 years old. Elderly patients (≥ 65 years old) may be more likely to experience adverse events, including cuSCC, decreased appetite, and cardiac disorders. The effects of Zelboraf on overall survival, progression free survival and best overall response rate were similar in the elderly and younger patients (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

Creatinine.

Creatinine increases, mostly cases of mild (> 1-1.5 x ULN) to moderate (> 1.5 - 3 x ULN) and mostly reversible in nature, have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Serum creatinine should be measured before initiation of treatment and periodically monitored during treatment as clinically indicated. For recommended dose modifications, see Section 4.2 Dose and Method of Administration, Dose modifications.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of vemurafenib on other medicinal products.

CYP1A2 inhibition was observed when a single dose of caffeine (CYP1A2 substrate) was coadministered after repeat dosing with vemurafenib for 15 days. This resulted in a 2.6-fold increase (geometric mean ratio) (maximum 5-fold) in caffeine plasma exposure after vemurafenib treatment. In another clinical trial, vemurafenib increased AUC_last and AUC_inf of a single 2 mg dose of tizanidine (CYP1A2 substrate) approximately 4.2 and 4.7-fold, respectively. Vemurafenib may increase the plasma exposure of substances predominantly metabolised by CYP1A2 and dose adjustments should be considered for CYP1A2 substrates with narrow therapeutic indices (such as theophylline, tizanidine, neuroleptics, including clozapine, olanzapine, carbamazepine and phenytoin, tricycle antidepressants, methadone, cyclosporine and warfarin) if coadministration cannot be avoided.
When a single dose of dextromethorphan (CYP2D6 substrate) was coadministered after repeat dosing with vemurafenib for 15 days, the plasma AUC of dextromethorphan and its metabolite dextrorphan increased by 47% (geometric mean ratio). The reason for this is unknown but does not appear related to CYP2D6 inhibition.
CYP3A4 induction was observed when a single dose of midazolam (CYP3A4 substrate) was co-administered after repeat dosing with vemurafenib for 15 days. This resulted a 39% decrease (geometric mean ratio) (maximum 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4 and dose adjustments should be considered for CYP3A4 substrates with narrow therapeutic indices. The efficacy of contraceptives metabolised by CYP3A4 may be decreased.
When a single dose of warfarin (CYP2C9 substrate) was coadministered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (18% for S-warfarin by geometric mean ratio). Exercise caution and consider additional INR monitoring when vemurafenib is used concomitantly with warfarin.
Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window should be made with caution since vemurafenib may increase their concentrations.
Due to the long half-life of vemurafenib, the full modulatory effect of vemurafenib on a concomitant medicine might not be seen for 8 days. After ceasing vemurafenib, a washout of 8 days may be needed to avoid an interaction with a subsequent treatment.

Effects of other medicinal products on vemurafenib.

Vemurafenib is a substrate of CYP3A4 and, therefore, concomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Coadministration of rifampin, a strong CYP3A4 inducer, significantly decreased the plasma exposure of vemurafenib (AUC) by approximately 40% following a single 960 mg dose of vemurafenib (see Section 5.2 Pharmacokinetic Properties, Metabolism). Coadministration of itraconazole, a strong CYP3A4 inhibitor, increased steady state vemurafenib AUC by approximately 40%. Caution should be used when vemurafenib is co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, phenobarbital, rifapentine, St John's wort [hypericin]). Dose reduction of vemurafenib may be considered during co-administration with a strong CYP3A4 inhibitor, if clinically indicated (see Section 4.2 Dose and Method of Administration, Dose modifications).

Interaction of vemurafenib with drug transport systems.

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporter P-glycoprotein (P-gp). Clinical drug interaction study GO28394 using a P-gp substrate drug (digoxin) demonstrated that multiple oral doses of vemurafenib (960 mg twice daily) increased the exposure of a single oral dose of digoxin, with an approximately 1.8 and 1.5-fold increase in digoxin AUC_last and C_max, respectively. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. Dose reduction of the concomitant P-gp substrate drug may be considered, if clinically indicated.
Vemurafenib is a weak P-gp substrate in vitro and its pharmacokinetics may be affected by medicines that inhibit or influence P-gp (e.g. verapamil, clarithromycin, ciclosporin, ritonavir, dronedarone, amiodarone, itraconazole, ranolazine). Concomitant administration of potent inducers of P-gp and vemurafenib should be avoided since the efficacy of vemurafenib may be reduced.
In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor of breast cancer resistance protein (BCRP). The effects of vemurafenib on drugs that are substrates of BCRP, and the effects of P-gp or BCRP inducers and inhibitors on vemurafenib exposure are unknown but vemurafenib may increase the exposure of coadministered drugs that are substrates for BCRP.
In vitro, at clinically-relevant concentrations, vemurafenib was an inhibitor of the bile salt export pump (BSEP).
In vitro, vemurafenib was not a substrate for OATP1B1 or OATP1B3. It is unknown if vemurafenib is a substrate to other transport proteins.

Potentiation of radiation toxicity.

Cases of radiation recall and radiation sensitisation have been reported in patients treated with radiation either prior, during or subsequent to Zelboraf treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens).
Zelboraf should be used with caution when given concomitantly or sequentially with radiation treatment. Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted with Zelboraf. No histopathological findings were noted in male and female reproductive organs at subclinical systemic exposures in repeat-dose toxicology studies.
(Category D)
Women of childbearing potential and men should use effective contraception while receiving Zelboraf and for at least 6 months after discontinuation of Zelboraf.
Zelboraf is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.
No clinical studies of Zelboraf in pregnant women have been performed, however placental transfer of vemurafenib to a fetus has been reported. Based on its mechanism of action, vemurafenib could cause fetal harm when administered to a pregnant woman. The teratogenic potential of vemurafenib has not been adequately evaluated in animal studies, although no unequivocal treatment related increases in the incidences of malformations were observed in the fetuses of rats at doses up to 250 mg/kg/day (approximately 1.4 times the human clinical exposure based on AUC) and rabbits at doses up to 450 mg/kg/day (approximately 0.5 times the human clinical exposure based on AUC).
It is not known whether Zelboraf is excreted in human breast milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or discontinue Zelboraf therapy after considering the benefits of breastfeeding for the child and the benefits of therapy for the mother.